Design and synthesis of renal dipeptidase inhibitors

Abstract

Aminophosphinic acid derivatives were synthesized as potential inhibitors of renal dipeptidase, an enzyme overexpressed in benign and malignant colon tumors. Several compounds showed potent enzyme-inhibitory activity. These compounds can be used therapeutically and diagnostically for treatment and detection of tumors.

1. A compound of formula I: 
                 
 
       wherein
 X is selected from the group consisting of F, Cl, Br,  125 I, I, CF 3 , NR′, and radioisotopes thereof;  
 Y is selected from the group consisting of H, CH 3 , OCH 3 , CF 3 , F, Cl,  125 I, NR′, and radioisotopes thereof;  
 NR′ is selected from NH 2 , N(C1 to C6 alkyl) 2 , and NH (C1 to C6 alkyl);  
 Z is selected from the group consisting of O, S, and radioisotopes thereof.  
 
     
     
       2. The compound of  claim 1  which is the E isoform. 
     
     
       3. The compound of  claim 1  which is the Z isoform. 
     
     
       4. The compound of  claim 1  which is radiolabeled. 
     
     
       5. The compound of  claim 1  wherein at least one atom of X or Y is radiolabeled. 
     
     
       6. The compound of  claim 1  wherein at least one of X or Y is an  125 I atom. 
     
     
       7. A sterile, apyrogenic formulation for intravenous administration to a human subject comprising:
 the compound of  claim 1 ; and  
 water.  
 
     
     
       8. The method of inhibiting colon tumor growth, comprising:
 administering to a subject carrying a colon tumor an effective amount of a compound of  claim 1 , whereby growth of the colon tumor is inhibited.